Idiopathic inflammatory diseases (IIDs) of the central nervous
system (CNS) comprise a broad spectrum of disorders which may be
differentiated according to the clinical presentation, neuroimaging and
pathological findings. Systemic autoimmune diseases including
vasculitis, Behcet's disease, antiphospholipid syndrome and
thyroiditis may also present with CNS manifestations and MRI findings of
hyperintense lesions in the CNS. Graves' disease is an autoimmune
thyroid disease that might involve CNS and orbits in the setting of
hyperthyroid, hypothyroid or euthyroid state. Findings of orbital
involvement are proptosis, dry eyes, strabismus, and optic neuropathy.
Recent literature has also proposed that altered thyroid function
homeostasis might trigger subsequent demyelination. Here, we report a
patient who presented with a hyperintense pontine lesion and ocular
findings in the setting of hyperthyroid state. We aim to further discuss
the underlying mechanisms leading to this presentation. (Archives of
Neuropsychiatry 2011;48: 274-6)

Idiopathic inflammatory diseases (IIDs) of the central nervous
system (CNS) comprise a broad spectrum of disorders which may be
differentiated according to the clinical presentation, neuroimaging and
pathological findings (1,2). Central pontine myelinolysis (CPM),
steroid-responsive encephalopathy associated with autoimmune thyroiditis
(SREAT), Bickerstaff's brainstem encephalitis (BBE) are some of the
disorders that might present with a localized lesion that specifically
involves the pontine area (3). Systemic autoimmune diseases including
vasculitis, Behcet's disease, and antiphospholipid syndrome may
also present with neurological signs and hyperintense lesions in the CNS
and these conditions should be considered in the differential diagnosis.
Autoimmune thyroid diseases may initially present with SREAT which is a
relatively rare condition. The clinical presentation consists of a
subacute, sometimes relapsing-remitting, steroid-responsive
encephalopathy with diffuse or focal neurologic signs, headache, altered
cognitive function, neuropsychiatric symptoms, diffuse
electroencephalographic abnormalities and elevated levels of antithyroid
antibodies. Recent literature has reported the pathological features of
SREAT as a complication of autoimmune thyroid disease. Biopsy showed
primary CNS demyelination and neuroimaging revealed responsiveness to
steroid treatment. The histopathological features included vasculitis
involving venules and arterioles, lymphocytic perivascular cuffs and
microglial activation (4). The pathogenesis of CNS manifestations of
autoimmune thyroid disorders remains to be unknown; however, vasculitis
and autoimmunity directed against common brain-thyroid antigens seem to
be the most probable responsible pathways (5). Recent literature has
also proposed that altered thyroid function homeostasis might be
responsible for triggering a subsequent demyelination process (6). The
clinical presentation has been attributed mostly to Hashimoto's
thyroiditis (HT) and less frequently to Graves' disease (GD) (5).
GD is also an autoimmune thyroid disease and the clinical presentation
might involve the orbits leading to proptosis, dry eyes, strabismus, and
optic neuropathy in the setting of hyperthyroid, hypothyroid or
euthyroid state (7). Altered consciousness, involuntary movements,
seizures, cognitive impairment, focal neurological signs, sensorial
alterations, headache and psychiatric alterations have been reported in
GD patients. Hyperintense white matter changes might be detected on MRI
and appear to be reversible as previously reported also in case of HT
(8,9).

In this article, we report a patient who presented with a
monophasic hyperintense pontine lesion and ocular findings in the
setting of a hyperthyroid state, and further discuss the underlying
mechanisms.

Case Report

A 47-year-old female presented with primary complaint of oblique
diplopia. The past medical and family history was non-remarkable. Her
neurological examination revealed right lower extremity weakness
(medical research council score of +4/5), however, cerebellar and
sensory findings were normal, plantar reflexes, deep tendon reflexes
were normoactive. Neuroophthalmological evaluation of the patient showed
normal visual acuity {VA: 20/20 OD (right) and 20/20 OS (left)} and
color vision (ISH 11/11 OU), fundus exam did not show any abnormality.
However, further exam showed mild proptosis with Hertel
exophthalmometric measures as: 20 OS, 24 OD, and restricted
supraduction, adduction OD in extraocular eye movements.

The patient was admitted to the hospital and methylprednisolone
(1000 mg, infusion, 3 days) and anti-thyroid treatments were initiated.
After completion of the pulse therapy, the patient was on oral
prednisolone that was gradually tapered. At discharge, 2 weeks after
initiation of therapy, the patient's complaints mostly resolved.
The final neurological examination revealed mild supraduction and
restriction of adduction OD as well as improved proptosis (Hertel
exophthalmometric exam: 20 OS, 22 OD). At the 6-month follow-up, thyroid
function tests normalized (T3: 2.5, T4: 1.2, TSH: 2.44). The
neuro-ophthalmological evaluation still revealed mild limitation in
adduction and supraduction OD and, proptosis remained to be improved
(Hertel exophthalmometric exam: 20 OS, 22 OD). No additional changes in
extra-ocular eye movements were observed and the follow-up cranial MRI
revealed that the hyperintense pontine lesion observed on T2 and FLAIR
images on previous evaluations completely alleviated (Figure 1).

Discussion

Idiopathic inflammatory diseases of the CNS represent a wide
spectrum of disorders with relatively specific clinical, laboratory and
imaging findings. Here, we report a patient with a monophasic CNS lesion
and a hyperthyroid state. Different entities might lead to localized
pontine lesions including multiple sclerosis (MS), variants of MS,
clinically isolated syndrome (isolated brainstem syndrome) or CNS
lymphoma. In our case, the clinical picture was not compatible with the
proposed diagnostic criteria for MS. The patient did not have any
previous signs and symptoms that could be attributed to MS. The CSF
evaluation was normal with no oligoclonal bands (OCB) and with normal
IgG index. Follow-up MRI of the patient did not reveal any dissemination
in space or time.

The clinical and MRI findings also precluded other possible
diagnosis for IIDs (acute disseminated encephalomyelitis or
neuromyelitis optica). A hyperintense lesion in the central pons is the
typical finding of CPM, which most commonly develops due to rapid
correction of hyponatremia. The other disorders that might lead to CPM
include malnutrition, chronic alcoholism, liver disease and organ
transplantation, however, our patient did not have any previous history
of the above mentioned disorders and the metabolic and hepatic panels
were all within normal limits. Lymphoma also responds rapidly to
corticosteroid treatment, however, a possible lymphoma was ruled out in
our patient with the lack of systemic findings and with normal
hematological evaluations. Differential diagnosis also included
neuro-Behcet's disease, CNS vasculitis and neurosarcoidosis,
however the immunological and serological evaluations, chest X-ray and
ACE levels were all within normal levels and these entities were ruled
out.

[FIGURE 1 OMITTED]

Previous reports have suggested a possible relationship between
autoimmune thyroid diseases and neurological involvement. GD is a
thyroid disorder caused by an antibody-mediated autoimmune reaction with
unknown etiology. Shared auto-antigens against the extraocular muscles
and thyroid trigger a cascade of events leading to involvement of
extraocular muscles and hyperthyroidism. Here, we present a patient with
hyperthyroidism and extraocular findings compatible with GD. GD presents
with lid retraction, exophthalmos, myopathy with muscle involvement that
can be detected by MRI and optic neuropathy (7). Some evidence suggests
that IgG plays an etiological role in the development of hyperthyroidism
in GD and thyroid stimulating immunoglobulin (TSI) seems to aid in
predicting relapse and identification of ophthalmic GD. GD may present
with normal TRabs or TSI levels in the early stage and high levels
([greater than or equal to] 130%) are observed in 90% of patients with
GD (10). Thus, our patient was diagnosed as having GD based on high
thyroid hormone and low TSH levels as well as TSI level in the upper
normal range (120%).

A recent study reported a patient with GD and Miller-Fisher
syndrome and discussed the presentation of peripheral nervous system
demyelination in the presence of thyroid disorders (11). Additionally, a
recent report presented a case of concomitant GD and clinically isolated
demyelinating disease in childhood linking thyroid and CNS dysfunction
(12). In our case, the patient had a hyperintense lesion in the pontine
area and the presenting symptom, subacute diplopia, might result from
brainstem involvement due to the localization of the lesion. However,
proptosis and eye movement dysfuctions seem to be more related to GD. It
might also be speculated whether the MRI finding was due to a metabolic
dysfunction secondary to the thyroid condition or was the expression of
a concomitant disease. Thyroid disorders should be considered in
patients with neurological dysfunction of unknown origin independent of
the functional status of the thyroid and the nature of the underlying
autoimmune thyroid disease itself.

It is important to consider the wide spectrum of symptoms that
might present with thyroid diseases in order to reach an accurate
diagnosis for prognostic and treatment implications.